CN1302004C - Preparing method for cytarabine - Google Patents
Preparing method for cytarabine Download PDFInfo
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- CN1302004C CN1302004C CNB031536921A CN03153692A CN1302004C CN 1302004 C CN1302004 C CN 1302004C CN B031536921 A CNB031536921 A CN B031536921A CN 03153692 A CN03153692 A CN 03153692A CN 1302004 C CN1302004 C CN 1302004C
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- Prior art keywords
- ara
- triazole
- ethyl ester
- cytosine arabinoside
- cytarabine
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Abstract
The present invention relates to a method for preparing cytarabine, which comprises the following steps: uracil arabinoside reacts with acetic anhydride or acetyl chloride or acetyl bromide in pyridinium to generate uracil arabinoside ethyl ester, the uracil arabinoside ethyl ester reacts with triazole compounds under the action of phosphorus oxychloride and inert organic solvent to generate triazole uridine, and the triazole uridine is ammonolyzed to generate cytarabine. The method of the present invention overcomes the defects of the prior art, the adopted solvent is cheap, the solvent consumption is little, the yield of the industrial preparation is high, and production cost can be effectively controlled; in addition, strong acidic cation-exchange resin is adopted to separate and purify cytarabine crude products, and obtained cytarabine products conform to requirements of European and American pharmacopoeias.
Description
Invention field
The present invention relates to chemical pharmacy field, particularly, the present invention relates to a kind of preparation method of nucleotide drug cytosine arabinoside.
Background technology
The chemistry of cytosine arabinoside is by name: the Arabic glycosyl cytidine(C of 1-β-D-, and English Cytarabine by name is called for short Ara-C, and its chemical structure is as follows:
Cytosine arabinoside is a kind of antiviral, also be used for antitumor, leukemia particularly.
The preparation method of the cytosine arabinoside of bibliographical information has:
1. be the complete synthesizing process (DE2027305A and DE2601399A) of raw material with the pectinose:
The preparation process of this law cyanoacetylene is longer, and need use the propine acid amides of easily blasting, and is difficult to adapt to suitability for industrialized production;
2. be raw material with the cytidine, synthesize cytosine arabinoside through cyclotidine:
This route, the method for bibliographical information is a lot.But both made is nearest document (US5610292A), and the yield of cyclotidine also has only 29%, and yield is very low, the cost height.In addition, because the cyclotidine open loop unavoidably some cytidines can occur,, be difficult to the refining pharmacopeia requirement that reaches because its character and cytosine arabinoside are closely similar;
3. be the synthetic cytosine arabinoside of raw material with the ara U:
In this route, when X=Cl (DE2146733A) or SH (US3116282A), need in autoclave, to seal ammonia and separate, severe reaction conditions, facility investment is big; Work as X=
The time (US4754026A), in preparation process, can by-product Repone K and water because the Repone K moisture absorption very easily, reaction system is difficult to separation and purification, is not suitable for suitability for industrialized production;
4. the direct ammonia of ara U is separated synthetic cytosine arabinoside (EP757056A):
This method seems simply, and yield is also high, but has two weakness: 1., need high-temperature pressurizing (135 ℃, 15bar) ammonia is separated, to the equipment requirements height; 2., owing to used the two silicon amine of hexamethyl (22.42 gram ara Us need with the two silicon amine of 187.5ml hexamethyl) in a large number, not only to environment cause bigger pollution and also because of a large amount of silicon compound of by-product to the ion exchange resin infringement greatly, so the cost height is uneconomical;
It is the method for the synthetic cytosine arabinoside of starting raw material with the uridine that 5.1982 year KJ Divakar etc. has reported, wherein comprised following operational path (J.Chem.Soc.Perkin.Trans 1 1982,1171-1176):
But this method is applied to industrial production exists following shortcoming:
1., the document is when preparation compound VI I, be that ara U and acetic anhydride are reacted in pyridine, the pyridine consumption has surpassed 1: 10 with the ara U ratio (the 26.5g ara U need restrain pyridines with 275) herein, because pyridine costs an arm and a leg, be difficult to reclaim, use so a large amount of pyridines not only environment to be impacted, and cost is increased greatly;
2., the document is when preparation Compound I X, be with the 1.2.4-triazole, after phosphorus oxychloride and triethylamine react in acetonitrile, react with compound VI I again, this method acetonitrile consumption is 1: 22 with the ratio of compound VI I, acetonitrile also is an expensive solvent, is difficult to recovery set usefulness in the reaction of this step, and the same reason also can make production cost increase; Also have so many solvents also to be unfavorable for cytosine arabinoside scale operation; In addition, in this method, the consumption of the reaction of this step triethylamine, phosphorus trichloride and 1.2.4-triazole is also bigger;
3., the document is with Compound I X elder generation and ammoniacal liquor dioxane mixture reaction when in the end a step prepares Compound I, react with methanol ammonia again, directly crystallization in ethanol after concentrated, the preparation cytosine arabinoside, herein not only the dioxane consumption big (with the amount ratio of Compound I X be 1: 10), cost height, and owing to lack effective method for purifying and separating, the gained cytosine arabinoside is of poor quality, does not reach American-European pharmacopeia requirement.
Goal of the invention
The objective of the invention is to overcome the deficiencies in the prior art, provide one be suitable for suitability for industrialized production easy, prepare the method for high quality cytosine arabinoside economically and reasonably.
Summary of the invention
The present invention is raw material with the ara U, by following reactions steps, prepares synthetic cytosine arabinoside:
Concrete steps are:
1, ara U is suspended in the pyridine, with acetic anhydride or Acetyl Chloride 98Min. or acetyl bromide reaction, concentrate the back refining compound VI I.Herein, the mole number of acetic anhydride or Acetyl Chloride 98Min. or acetyl bromide is 1 with the ratio of ara U: 1.25-1: 9, be preferably 1: 3-1: and 6, be preferably 1: 3-1: 4.5; The weight ratio of pyridine and cytosine arabinoside is 1: 1-1: 10, be preferably 1: 2-1: 4; Temperature of reaction is 0-100 ℃;
2,1.2.4-triazole (R=H) or 3-nitro-1.2.4-triazole (R=NO2) and phosphorus oxychloride are dissolved in inert organic solvents, cooling drips triethylamine, behind the adding compound VI that the finishes I, 0-60 ℃ of reaction 1-20 hour, after washing concentrates, get compounds X; Inert organic solvents is meant C herein
1-C
4Halogenated alkane or the ester that forms of the alcohol of the acid of the ether of the ketone of C3-C10 or C4-C12 or tetrahydrofuran (THF) or dioxane or C1-C8 and C1-C8.The halogenated alkane of C1-C4 is meant but not only follows in methylene dichloride, chloroform, 1.1.1-trichloroethane etc. herein; The ketone of C3-C 10 is meant but is not limited only to acetone, butanone, hexone etc.; The ether of C4-C12 is meant but is not limited only to ether, dipropyl ether, diisopropyl ether, methyl tertiary butyl ether etc.The ester that the acid of C1-C8 and the alcohol of C1-C8 form is meant but is not limited only to ethyl acetate, butylacetate, tert.-butyl acetate etc.Inert organic solvents total amount (volume ml) is 1 with the ratio of compound VI I (weight g): 5-15.
3, with after compounds X and ammoniacal liquor dioxane or the reaction of ammoniacal liquor tetrahydrofuran compound, concentrate, react with methanol ammonia again, reconcentration, after the residue water dissolution, last Zeo-karb, wash the removal of impurity earlier with water, use the alkaline eluant wash-out again, after elutriant concentrated, water-acetone or water-ethanol were refining as to meet American-European officinal ara U.Zeo-karb is meant on vinylbenzene-divinylbenzene interpolymer and has sulfonic Zeo-karb herein, and its degree of crosslinking is between 2%-10%, and granular size is between the 50-1000 order.Refer to 001X2 as homemade tree, 001X4,001X8; Import resin such as DOWEX 50W series, Amberlite IR-120, Lewatit-100, Diaion SK-1 etc.Alkaline eluant is meant the organic amine aqueous solution of the C1-C9 of the ammoniacal liquor of 0.1%-10% or 0.1%-10%.Wherein the organic amine of C1-C9 is meant that load is not limited only to methylamine, ethamine, dimethylamine, triethylamine, thanomin or their mixture etc.
Compare the following advantage of the inventive method tool with method of the prior art:
1, the inexpensive amount of solvent selected for use of the present invention is few, and preparation of industrialization yield height can effectively be controlled production cost;
2, the present invention selects for use storng-acid cation exchange resin separation and purification cytosine arabinoside crude product can obtain meeting the cytosine arabinoside finished product of American Pharmacopeia.
The invention will be further described below by embodiment.It should be understood that the described preparation method of the embodiment of the invention is only used for illustrating the present invention, rather than limitation of the present invention, the simple modifications to preparation method of the present invention under design prerequisite of the present invention all belongs to the scope of protection of present invention.Except as otherwise noted, the percentage ratio among the present invention is weight percentage.
Embodiment 1: the preparation of ara U ethyl ester (compound VI I):
Pyridine 26.2kg is added in the retort, stir, add ara U 11.5kg, acetic anhydride 18.6kg successively, stirring at room reaction 3 hours.Reaction is finished, and adds 11.5 liters of methyl alcohol, stirs 0.5 hour, is evaporated to pyridine and can steam.Add the dissolving of ethanol stirring heating.Be chilled to below 0 ℃ and spend the night.Discharging, suction filtration, oven dry get compound VI I 15.8kg, yield 91%.
Embodiment 2: the preparation of triazole uridine (Compound I X):
Chloroform 150L is added retort, stir, add triazole 15kg.Be chilled to below 5 ℃, add phosphorus oxychloride 9.225kg.Finish phosphorus oxychloride, continue to be stirred to below 5 ℃, drip triethylamine 33.75L.The control rate of addition makes the highest intensification be no more than 8 ℃.15kg adds in the above-mentioned retort with ara U ethyl ester (compound VI I).Stirred overnight at room temperature.React completely, add entry 150L, stir, emit chloroform layer.Water chloroform 60L * 2, extracting twice merges anhydrous magnesium sulfate drying with organic phase and chloroform layer.Suction filtration, filtering sal epsom, filtrate adds dehydrated alcohol after concentrating dried chloroform, the stirring and refluxing dissolving.Be chilled to below 0 ℃ and spend the night.Suction filtration leaches solid, and after solid washed with small amount of ethanol, oven dry (70 ℃) got triazole uridine (Compound I X) 14.3kg, yield 84%.
Embodiment 3: the preparation of cytosine arabinoside:
Dioxane 68.5kg is added retort, open stirring and be chilled to 15 ℃, logical ammonia 5～6 hours.Add triazole uridine (compounds X) 13.7kg and ammoniacal liquor 9.6kg, stirred overnight at room temperature.The concentrating under reduced pressure dioxane distillates to no longer including liquid.Add methanol ammonia 54.8kg, reaction is spent the night.Reaction is finished, and is evaporated to dried.Residue is dissolved in deionized water 60L, last 001X4 ion exchange resin.Use earlier deionized water drip washing, the back contains the product elutriant with 5% weak ammonia wash-out, collection, and reduced vacuum is concentrated into to do and is crude product.Crude product water alcohol reflux is dissolved.Filtered while hot, filtrate are advanced smart baking bag crystallizer.Crystallization is spent the night.Suction filtration leaches crystallization, and crystallization is with after the small amount of ethanol washing, dry cytosine arabinoside 5.75kg, yield 70%, the full inspection of product meets the American Pharmacopeia requirement.
Claims (4)
1. a method for preparing cytosine arabinoside comprises the following steps:
A. ara U and acetic anhydride are reacted in pyridine, obtain the ara U ethyl ester;
Ara U ara U ethyl ester
B. the reaction under phosphorus oxychloride, triethylamine and inert organic solvents chloroform give are used with ara U ethyl ester and 3-triazole compounds obtains the triazole uridine;
Ara U ethyl ester triazole uridine
C. the triazole uridine being carried out ammonia with methanol ammonia separates and obtains cytosine arabinoside;
Triazole uridine cytosine arabinoside
It is characterized in that:
Among the step a, the weight ratio of ara U and acetic anhydride is 11.5: 18.6; The weight ratio of ara U and pyridine is 11.5: 26.2;
Among the step b, the volume of inert organic solvents chloroform (liter) is 10L: 1kg with the ratio of the weight (kilogram) of ara U ethyl ester, and 3-triazole compounds is 1.2.4-triazole or 3-nitro-1.2.4-triazole;
Among the step c, after reaction solution concentrates, go up Zeo-karb with the less water dissolving, wash out impurity with water, obtain cytosine arabinoside with alkaline eluent wash-out again, wherein the Zeo-karb among the step c is to have sulfonic Zeo-karb on vinylbenzene-divinylbenzene interpolymer, and its degree of crosslinking is between 2%-10%, and granular size is between the 50-1000 order.
2. according to the process of claim 1 wherein that the temperature of reaction of step a is 0-100 ℃.
3. according to the method for one of claim 1-2, wherein in step c, alkaline eluent is that weight percentage is that ammoniacal liquor or the weight percentage of 0.1%-10% is the C of 0.1%-10%
1-C
9The organic amine aqueous solution.
4. according to the method for claim 3, C wherein
1-C
9Organic amine be methylamine, ethamine, dimethylamine, triethylamine, thanomin or their mixture.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB031536921A CN1302004C (en) | 2003-08-22 | 2003-08-22 | Preparing method for cytarabine |
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| Application Number | Priority Date | Filing Date | Title |
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| CNB031536921A CN1302004C (en) | 2003-08-22 | 2003-08-22 | Preparing method for cytarabine |
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| CN1583776A CN1583776A (en) | 2005-02-23 |
| CN1302004C true CN1302004C (en) | 2007-02-28 |
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| CNB031536921A Expired - Lifetime CN1302004C (en) | 2003-08-22 | 2003-08-22 | Preparing method for cytarabine |
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| WO2020117988A1 (en) | 2018-12-04 | 2020-06-11 | Tolero Pharmaceuticals, Inc. | Cdk9 inhibitors and polymorphs thereof for use as agents for treatment of cancer |
| WO2020191326A1 (en) | 2019-03-20 | 2020-09-24 | Sumitomo Dainippon Pharma Oncology, Inc. | Treatment of acute myeloid leukemia (aml) with venetoclax failure |
| CN112552361A (en) * | 2020-12-30 | 2021-03-26 | 瀚晖制药有限公司 | Cytarabine crystal, cytarabine freeze-dried powder and freeze-drying method |
| CN113372401A (en) * | 2021-04-13 | 2021-09-10 | 国药一心制药有限公司 | Novel crystal form of cytarabine and preparation method thereof |
| CN113292611B (en) * | 2021-06-25 | 2022-05-17 | 国药一心制药有限公司 | Cytarabine purification method |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3116282A (en) * | 1960-04-27 | 1963-12-31 | Upjohn Co | Pyrimidine nucleosides and process |
| US5359067A (en) * | 1991-11-23 | 1994-10-25 | Hoechst Aktiengesellschaft | Process for the preparation of 5-substituted cytosines and other 4,5-disubstituted pyrimidin-2(1H)-ones, and intermediates arising in the course of this |
| EP0757056A1 (en) * | 1995-08-03 | 1997-02-05 | PRO.BIO.SINT. S.r.l. | Method for preparing 1-beta-D-arabinofuranosylcytosine |
-
2003
- 2003-08-22 CN CNB031536921A patent/CN1302004C/en not_active Expired - Lifetime
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3116282A (en) * | 1960-04-27 | 1963-12-31 | Upjohn Co | Pyrimidine nucleosides and process |
| US5359067A (en) * | 1991-11-23 | 1994-10-25 | Hoechst Aktiengesellschaft | Process for the preparation of 5-substituted cytosines and other 4,5-disubstituted pyrimidin-2(1H)-ones, and intermediates arising in the course of this |
| EP0757056A1 (en) * | 1995-08-03 | 1997-02-05 | PRO.BIO.SINT. S.r.l. | Method for preparing 1-beta-D-arabinofuranosylcytosine |
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